CS209466B2 - Method of making the alpha-alkylaminopropiophenon derivatives - Google Patents

Description

It is an object of the present invention to provide novel N-alkylaminopropiophenone derivatives.

It has been found that two novel compounds of formula (I)

co-CHCH ₃ -NH »c (CH $ pharmaceutical purposes, see for example British Patent Nos 768772, 1011289 and 1069 797. The efficacy of both the new compounds according to the invention is excellent and known related compounds do not.

These compounds can be prepared by procedures known for this kind of compounds.

A suitable method is to oxidize the corresponding secondary amino alcohol of formula (VIII) (I) wherein:

X is chlorine or fluorine, and their acid addition salts have valuable properties as antidepressants in standard anti-depressant efficacy assays, for example, in a rodent calming test induced by tetrabenazine. In particular, it has been found that the compounds of formula I require much higher doses for a stimulant effect than an antidepressant effect. These compounds are also not monoamine oxidase inhibitors, nor do they have a pressor effect.

The bleach-related alkylaminopropiopheas are already known and have been designed for various 209466

NHClCH where

X is as defined above.

The oxidation may conveniently be carried out by known methods, in particular by an Oppenauer oxidation reaction using an excess of a ketone, for example acetone or cyclohexanone, in the presence of an aluminum alkoxide, for example alumnium isopropoxide. a line of known possibilities is the use of an acidic solution of an alkali metal chromate, for example sodium.

After isolation, the mXa-tert-butylaminopropiophenones of formula I are stable and can be distilled under reduced pressure, although this is not usually required, are slightly weak bases (pKa / about 8.5 to 9) and are preferably stored and applied in a similarly pharmaceutically acceptable salts, preferably mineral acid salts such as the hydrochloride salt. Under physiological conditions, they will be predominantly (but not exclusively) cationic, but in all cases, when administered in the form of a single salt, will be in equilibrium with different anions corresponding to other acids present in the body and their salts with different acids may only be beneficial It is understood that all salts of the bases of formula I with non-toxic acids are equivalent to each other and with respect to the bases.

It goes without saying that acid salts that are not pharmaceutically innocuous may also be valuable intermediates for the preparation of the innocuous salts by double decomposition, alkaline exchange, and other known methods.

The process of the invention provides a compound of formula I and pharmaceutically acceptable salts thereof.

The invention also provides pharmaceutical compositions (preferably in unit dosage form) comprising a compound of formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. Preferably, the compound of formula (I) or an addition salt thereof comprises 5 to 95 wt. percent of said composition.

The invention further provides a method of treating a depressive condition in a mammal, such as a human, mouse, rat, etc., comprising administering an effective non-toxic amount (dose) of an antidepressant, preferably in the form of a unit dose of a compound of formula I or a pharmaceutically acceptable salt thereof.

The compounds of formula I (active ingredients) or pharmaceutically acceptable salts thereof are preferably administered to a mammal in unit dosage form.

The compounds of the invention may be administered orally, parenterally or rectally.

Pharmaceutical compositions comprising the compounds of Formula I or the pharmaceutically acceptable salts thereof can be administered in dosage units such as tablets, capsules, ampoules, or suppositories, each or each containing an effective antidepressant innocuous amount of the compound.

A preferred dose for parenteral administration of a compound of Formula I (contemplated as a base) is about 5 mg / kg to 50 mg / kg of mammalian body weight, with a most preferred dose being 15 mg / kg to 35 mg / kg of mammalian body weight.

For oral or rectal administration, a preferred dose of a compound of formula I (considered as a base) is 10 mg / kg to 100 milligrams per kg of mammalian body weight, while a most preferred dose of a compound of formula I (considered as a base) is 30 milligrams per kg to 70 mg / kg body weight of mammal. The compound of formula (I) or the acid addition salt is preferably administered 4X daily, although the number of daily applications may vary depending on the condition of the patient (mammal) and at the discretion of the attending physician. For human administration, the preferred dose of a compound of Formula I or an acid addition salt thereof (contemplated as a base) for oral administration or suppository administration is about 15 to 500 mg, with a more preferred unit dose being 100 to 300 mg and the most preferred dose being 125 to 250 mg. All of the above dosages express the weight of the compound of formula (I) in the form of its base, but as indicated above, the compound is preferably used in the form of its pharmaceutically acceptable acid addition salt.

The compound of Formula I, or a pharmaceutically acceptable salt thereof, may be administered in the form of an oral unit formulation (e.g., as a tablet or capsule) containing one or more pharmaceutically acceptable carriers, which may be in the form of a solid diluent such as lactose, corn starch, finely divided silica gel. as well as other excipients used in formacology for this purpose.

For rectal use, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be in the form of a suppository with conventional pharmaceutically acceptable carriers such as cocoa butter, and for parenteral use may be in the form of ampoules with sterile solutions or suspensions in water or other pharmaceutically acceptable liquids as carriers. , or as an ampoule of sterile powder for dilution with a pharmaceutically acceptable liquid.

Of course, in addition to the above ingredients, the pharmaceutical compositions of the invention may contain one or more other ingredients such as diluents, buffering agents, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives, etc. These pharmaceutical compositions may be prepared by admixing additives and, if necessary, shaping the resulting mass and filling it into suitable containers or containers.

The compound of formula I is preferably used for the treatment of depressive states in the form of a pharmaceutically acceptable salt. Examples of some pharmaceutically acceptable salts which may be used are salts of the following acids: hydrochloric acid, sulfuric acid, phosphoric acid and toluenesulfonic acid.

The invention is illustrated by the following examples:

Example 1

Preparation of dl-m-chloro-α-tert-butylaminopropiophenone hydrochloride

To a vigorously stirred solution of 1.0 g of dl-erythro-α- (m-chlorophenyl) -5-tert-butylaminopropanol hydrochloride, m.p. 223 DEG-224 DEG C., in 5 ml of acetic acid, at 45 DEG-50 DEG C., respectively, and A solution of 0.5 g of sodium dichromate in 5 ml of acetic acid and 25 ml of 10% sulfuric acid is added in portions over one hour. After the addition was complete, stirring was continued for one hour at the same temperature, followed by ultraviolet absorption.

Amax. (nm.) ε 211 22,900 253 12,200 304 1,460

200 g of ice are added, the mixture is made strongly alkaline and extracted three times with 250 ml of ether each time. The combined extracts were dried over potassium carbonate and filtered, and the product, dl-m-chloro-α-tert-butylaminopropiophenone hydrochloride, was precipitated by bubbling dry hydrogen chloride gas through the filtrate.

The melting point after recrystallization from an ethanol / ether mixture is in the range of 233 to 234 ° C. Analysis for C 13 H 19 NOCl 2

Calculated:

C 56.53, H 6.93, N 5.07%;

Found:

C 56.74, H 7.03, N 4.85%.

spectrum in water

Amin. (nm.) ε

228 2,762

280 1,050

Nuclear magnetic resonance spectrum

This spectrum corresponds to the assumed structure

Example 2

Preparation of m-chloro-α-tert-butylaminopropiophenone

A homogeneous solution of 1.5 g of freshly distilled dl-erythro- (m-chlorophenyl) -S-tert-butylaminopropanol, 3.0 g of freshly distilled aluminum isopropoxide and 50 ml of anhydrous benzene are stirred and kept at 50 ° C in fitted with a condenser and a drying tube.

A 1 ml sample is then taken at regular intervals and treated with 1 ml of a 5% aqueous hydrochloric acid solution at pH 2. The resulting solution is then evaporated at 50 ° C under reduced pressure to give a pale yellow oily liquid which is collected by filtration. dissolved in 95% ethanol. The ultraviolet absorption spectra of the samples thus treated are measured and then compared with the quantitative absorption spectra of m-chloro-α-tert-butylaminopropiophenone (A), dl-erythro-α- (m-chlorophenyl) -3- tert -butylaminopropanol (B). , equimolar mixtures of (A) and (Bj and tert-butylammonium m-chlorobenzoate. After 3 hours, the reaction mixture is characterized by low absorption at A 240. Very small amino alcohol peaks at λ 278, 280 are discernible. the reaction products and the starting materials do not show any significant absorption in this area except for the aminoketone produced ε - 10 600 at λ 247, the observed results indicate the presence of the desired product.

Method of production

Lacitose, corn starch and said salt are mixed together and granulated with a binder, i.e. polyvinylpyrrolidone, in an alcoholic solution to form granules. The granules are passed through a 16-20 mesh screen, allowed to air dry, finely powdered sillkagel is added, and tablets are compressed. The tablets may then optionally be coated.

Example 3

Capsules weighing 400 mg

150 mg of the hydrochloride of the compound of the formula I are mixed with 125 mg of lactose and 125 mg of corn starch. The mixture is filled with hard gelatin capsules consisting of two halves.

Example 4

Parenteral solution

150 mg of the hydrochloride of the compound of formula I are dissolved in sterile water, U.S.P. so as to obtain 1 ml of solution. The preparation may contain bacteriostats in an amount of, for example, 0.2 to 0.5% w / v.

Example 5

Suppository weighing 400 mg

150 mg of the hydrochloride of the compound of the formula I are mixed with 250 mg of soft or melted cocoa butter and poured into a torch and cooled to form a suppository.

Claims (4)

SUBJECT VYNALEZU A process for the preparation of α-alkylaminopropiophenone derivatives of the general formula I (I) wherein X is chlorine or fluorine, or acid addition salts thereof, characterized in that the secondary alcohol of the formula X is as defined above, or an acid addition salt thereof is oxidized to a compound of Formula I or an acid addition salt thereof. 2. The process of claim 1 wherein the oxidation is carried out using an aluminum alkoxide in the presence of a ketone. 3. A process according to claim 2 wherein the aluminum alkoxide is aluminum isopropoxide and the ketone is acetone. 4. The process of claim 1 wherein the oxidation is performed using an acidic solution of sodium dichromate. CHOH.CHCHs NHClCHF 6